Project Summary This K23 award advances the Candidate's long term goal of integrating pharmacogenetic and psychiatric genetic approaches in the study of smoking/nicotine dependence (ND) and its co-occurrence with Attention Deficit Hyperactivity Disorder (ADHD). The proposed training will enable the PI to develop the skills needed for an independent interdisiplinary research career in this field. Risk for smoking behaviors in adolescents, including earlier age of initiation and likelihood of regular smoking, has been associated with both a clinical diagnosis of ADHD and non-clinical levels of ADHD symptoms. Several converging lines of work suggest that the high rates of smoking in the presence of ADHD symptoms may be related to common genetic vulnerabilities that increase risk for both ND and ADHD. In addition, increased risk for smoking in this population may be related to the effects of nicotine and nicotine abstinence on ADHD-related deficits in executive function (EF) and delay discounting (DD). The research plan focuses on elucidating a neurobiological pathway to ND by examining the genetic and cognitive correlates of smoking in adolescents with ADHD. First, secondary analysis of extant geneticially-informative samples will be conducted to address gaps in the literature related to 1) the latent genetic, environmental, and gene by environmental influences on the overlap between smoking/ND and ADHD and 2) associations with measured genetic variation related to the neuropharmacology of nicotine (i.e. dopaminergic, nicotinic acetylcholinergic, and nicotine metabolism genes) and the ND/ADHD comorbidity. Few genetic studies have examined ADHD and smoking concurrently and this work will assist in characterizing phenotypes and selecting measured genes most relevant to this etiological pathway, that is, adolescent smoking in the presence of ADHD symptoms. Second, new data will be collected using laboratory pharmacology methods to probe the cognitive and genetic mechanisms underlying increased risk for smoking in adolescents with ADHD by assessing the effects of nicotine abstinence on EF and DD in adolescent smokers with and without ADHD. EF and DD performance will be compared in adolescent smokers with (n=32) and without (n=32) ADHD after 24-hour biochemically verified smoking abstinence in the following conditions: 1) placebo patch (nicotine abstinence) and 2) 14 mg nicotine patch (nicotine replacement). DNA will also be collected in order to test the moderating role of genetic variation related to nicotine neuropharmacology on EF and DD processes. Results will inform a critical vulnerability for nicotine use in a high risk population, i.e. adolescents with ADHD, and advance the understanding of etiological factors in ND more broadly. This research will lead to subsequent grant applications to further probe genetic and neuropharmacological mechanisms associated with smoking risk in the presence of ADHD as well as clinical projects to develop more effective interventions for ND in this high- risk group. To enable the PI to pursue this long-term research agenda, she will work with experienced mentors to build upon her current expertise in neurocognitive phenotypes of ADHD with five areas of training: (1) nicotine psychopharmacology, 2) laboratory methods in behavioral pharmacology, 3) special issues in adolescent smoking research, 4) behavioral genetic analytic approaches, and 5) synthesizing these training experiences into a long-term pharmacogenetics of ND research program. Taken together, the proposed research and training plans address a key priority of integrating genetic and pharmacological methodologies to advance the understanding of etiological and treatment factors in ND, and it will fully prepare the PI for an independent clinical research career in the field.